Functional capacity, lung function, and muscle strength in patients undergoing hematopoietic stem cell transplantation: A prospective cohort study.

OBJECTIVE/BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a treatment for benign and malignant hematological diseases. These aggressive treatments cause reduced levels of physical activity, decreased lung function, and worse quality of life. Alterations in pulmonary function tests before HSCT are associated with the risk of respiratory failure and early mortality. The objective of this study was to evaluate functional capacity and lung function before and after HSCT and identify the predictors of mortality after 2 years. METHODS: A prospective cohort study was carried out with individuals with oncohematological diseases. The evaluations were carried out in two moments during hospitalization and at hospital discharge. Follow-up was carried out after 48 months. Assessments were carried out on 34 adults, using spirometry, manovacuometry, 6-Minute Walk Test (6MWT), Handgrip Strength Test, and 30-Second Chair Stand Test (30-s CST). RESULTS: There was a statistically significant reduction for the variables in forced vital capacity, forced expiratory volume predicted in the 1st second, Tiffeneau index, handgrip strength, and distance covered (% predicted) on the 6MWT (p < .05). There was a significant difference in the 30-s CST when individuals were compared according to the type of transplant. We found that a 10% reduction in the values of maximum inspiratory pressure (MIP) can predict an increased risk for mortality. CONCLUSIONS: Individuals undergoing HSCT have reduced functional capacity, lung function, and muscle strength during the hospitalization phase. Reduction in the values of MIP increases the risk of nonrelapse mortality.

Proliferative effects of five traditional Nigerian medicinal plant extracts on human breast and bone cancer cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal plants Hunteria umbellata (HUL), Cola lepidota (CCL), Persea americana leaf (PAL), Root bark of Persea americana (RPA) and Plukenetia conophora (PCL) are used in Nigerian traditional medicine for the treatment of cancer and cancer related diseases. AIM OF THE STUDY: To scientifically evaluate the cell proliferative and apoptotic effects of the plants extracts using breast and osteocarcinoma cell lines, and also to identify the possible components via LC-MS to have a kind of chemical fingerprint. MATERIALS AND METHODS: The antiproliferative and apoptotic effects of methanolic extracts (10 µg/ml) of the five medicinal plants were subjected to in vitro evaluation using four cancer cell lines (breast-MCF-7 and BT-20; Osteocarcinoma-MG-63 and Saos-2) measured by flow cytometry. Non-tumorigenic controls MCF-12A and primary isolated osteoblasts (POB) were chosen to eliminate negative influence on healthy tissue. RESULTS: Of the five extracts RPA demonstrated a significant (P<0.05) anti-proliferative activity against estrogen receptor positive breast cancer cell lines (MCF-7). The proliferative phase was decreased by 18%, whereas, a significant increase in cell proliferation (about 27%) was observed for RPA at a concentration of 10 µg/ml. PCL, CCL, HUL and PAL did not show marked inhibition of the proliferation of cell line MCF-7. CONCLUSION: These results give suggestive evidence that the plant extracts exhibit some correlation between the claimed ethnomedicinal uses and the cell proliferative activity. RPA extract includes chemical compounds with estrogen-like activity and validates its potential use as anticancer agent, particularly against breast carcinoma; provided important information potentially helpful in drug designing and discovery. Further studies will involve the isolation of anti tumour compounds in RPA by LC-MS and detailed mechanism of anticancer activities.

Noradrenergic modulation of avian kidney function.

Norepinephrine (NE) infused at doses of 0.7, 2.2 and 6.7 micrograms/min/kg body weight into conscious, salt and water loaded ducks dose-dependently induced arterial hypertension, reflex bradycardia and diuresis/natriuresis at unchanged glomerular filtration and reduced renal blood flow. NE-induced changes in plasma concentrations of osmoregulatory hormones consisted of a slight increase for the antidiuretic hormone, no change for angiotensin II and a nearly 4-fold increase for atrial natriuretic factor. Sub-pressor doses of NE infused close to the origin of the renal arteries induced diuresis without a rise in urinary sodium concentration. The results suggest pressure diuresis in ducks as a response to hypertensive NE doses with a possible contribution of atrial natriuretic factor to natriuresis.

Disinhibition of AVP release during noradrenaline and angiotensin II infusions in dogs by maintaining normotension with sodium nitroprusside.

Noradrenaline (NA) and angiotensin II (A II) were infused intravenously in conscious dogs without (series I) and with (series II) additional infusions of sodium nitroprusside at doses re-establishing normal levels of mean arterial pressure (MAP). In series I, NA infusion (1.6 micrograms/min per kg for 30 min) initially elevated MAP by some 25 mm Hg and lowered heart rate by some 30 beats/min. Plasma concentrations of arginine vasopressin (AVP) remained constant, while those of A II and atrial natriuretic factor were slightly, but significantly, increased. Infusion of A II (10 or 20 ng/min per kg for 30 min) induced similar rises in MAP and slight reductions of heart rate and increased plasma AVP by 70% and atrial natriuretic factor by 60%. In series II, sodium nitroprusside (1-4 micrograms/min per kg) was added for 30 min to infusions of NE (1.6 micrograms/min per kg) and A II (20 ng/min per kg) in order to maintain MAP at its control level. This resulted in an 11-fold increase in plasma AVP during NA infusion and a 19-fold increase during A II infusion. Infusing sodium nitroprusside (4 micrograms/min per kg) alone lowered MAP to clearly hypotensive levels, but the resulting rises in plasma AVP were less than, rather than equal to, those seen at normotensive MAP levels during the combined infusions of sodium nitroprusside with A II or NA, respectively. It is concluded that both NA and A II exert strong stimulatory actions on AVP release which are, however, counteracted by inhibitory influences arising from the hypertensive effects of NA and A II.

Central ANP administration in conscious dogs responding to dehydration and hypovolemia.

Eighteen beagles were chronically instrumented with an anterior third ventricular (A3V) infusion device to analyze, in conscious dogs, the involvement of central atrial natriuretic peptide (ANP) in body fluid and blood pressure control. The dogs' osmotic and body fluid homeostasis was challenged by 24 h water deprivation or blood withdrawal (12 ml/kg body wt) to elucidate possible modifying influences on the release of arginine vasopressin (AVP), angiotensin II (ANG II), and drinking. Three series of experiments were performed: 1) infusion of ANP (500 ng/min) dissolved in artificial cerebrospinal fluid (aCSF) and given for 10 min, 2) infusion of aCSF alone for the same length of time, and 3) time control experiments without infusion. Plasma AVP and ANG II were analyzed by radioimmunoassay, and in several experiments on dehydrated dogs, plasma norepinephrine and epinephrine were additionally determined by high-performance liquid chromatography. Various blood parameters and rectal and ear skin temperatures were measured. Arterial pressure and heart rate were recorded in three animals additionally equipped with carotid loops. Changes in plasma AVP and ANG II induced by dehydration and bleeding were not significantly modified by A3V infusions of ANP and aCSF in comparison to time controls. Blood pressure changes were similar in experiments with A3V ANP infusion and time controls during bleeding and reinfusion. It is concluded that central ANP is not important in the control of vasopressin and renin-angiotensin systems during osmotic and volume challenges in conscious dogs.

Ionic responsiveness in third ventricular hypertonic stimulation of antidiuresis in ducks.

Domestic ducks were chronically equipped with a device probing the third cerebral ventricle (VIII) for localized intracerebroventricular (i.c.v.) perfusion. In conscious animals made diuretic by intravenous water loading with 1.0 ml/min hypoosmotic glucose solution (200 mOsm/kg), hyperosmotic i.c.v. stimulations were tested for antidiuretic actions. Artificial cerebrospinal fluid made hypertonic (400 mOsm/kg) by adding sucrose, mannitol, NaCl, LiCl, choline chloride, NaI, NaNO3, LiNO3, CaCl2 or MgCl2 was perfused i.c.v. for 10-15 min at rates of 10-15 microliters/min. Arterial pressure and heart rate were monitored continuously. Hyperosmotic stimulations with non-electrolytes did not induce antidiuresis. Approximately equivalent degrees of antidiuresis were elicited by Na(+)-, Li(+)- and choline salts with a tendency for moderate rises in arterial pressure. Compared to Cl(-)- and I(-)-salts, the effects of NO3(-)-salts were attenuated. Divalent cations caused prolonged antidiuresis, sometimes preceded by initial diuresis, with circulatory side effects unrelated to the changes in renal fluid excretion. It is concluded that the observed antidiuretic effects were mediated by cation-sensitive, rather than osmosensitive neurons on the brain side of the blood-brain-barrier. Their transduction mechanism might consist of poorly selective membrane channels permeable to cations but not to anions.

Functional hypothalamic angiotensin II and catecholamine receptor systems inside and outside the blood-brain barrier.

To elucidate the contribution of various hormones and neuromodulators in the central nervous control of body fluid homeostasis, the saltwater-acclimated Pekin duck represents an ideal model due to the cytoarchitecture of its hypothalamus, and the marked systemic and hypothalamic sensitivity of its osmoregulatory system. Employing animal physiology, electrophysiology, histochemistry and receptor binding techniques, the role of angiotensin II (A II) and norepinephrine (NE) as both circulating hormones and neurotransmitters in central osmoregulation through interaction with neuronal targets inside and outside the blood-brain barrier (BBB) could be investigated. Application of both agents into the systemic circulation or into the cerebrospinal fluid of conscious animals, and the monitoring of hypothalamo-neurohypophyseal antidiuretic hormone ADH (= AVT) release, cardiovascular parameters such as mean arterial pressure (MAP) and avian salt gland function allowed to discriminate between actions of A II and NE at sites within or outside the BBB. Of the latter, the median eminence (ME), the subfornical organ (SFO) or the organum vasculosum laminae terminalis (OVLT) are of prime importance. Receptor autoradiography using radioiodinated ligands specific for A II, alpha 1-, alpha 2- and beta-receptors including the pharmacological characterization of these binding sites permit to establish a molecular correlate of the modulatory actions of both A II and NE.

ADH, renal, and circulatory responses to adrenergic stimulation in anterior third ventricle.

The anterodorsal part of the third ventricle of conscious ducks was perfused intracerebroventricularly (icv) for 10 min with norepinephrine (NE) or with its agonists phenylephrine (alpha 1, Phe), isoproterenol (beta, Iso), and clonidine (alpha 2, Clo) in artificial CSF (aCSF). Their effects on the plasma level of antidiuretic hormone (AVT, arginine vasotocin in birds), urine excretion, heart rate (HR), and mean arterial pressure (MAP) were investigated in steady-state water diuresis. The correct position of the icv cannula was confirmed by enhanced AVT release and antidiuresis in response to icv perfusion of aCSF made hypertonic (400 mosmol/kgH2O) by adding NaCl. Icv perfusion with hypertonic aCSF and 750 ng/min NE had comparable effects on AVT release and urine excretion, but hypertonic aCSF caused small increases in MAP and HR, whereas NE depressed both MAP and HR. Antidiuresis and circulatory depression caused by NE icv perfusion was dose dependent. Among the adrenergic agonists perfused at similar doses (188 ng/min), only Iso stimulated AVT release. Iso and Phe had small depressive effects on MAP and HR (less than 10%). Clo depressed circulation by greater than 20% for longer than 60 min, and AVT release became significantly reduced 30 min after the start of icv perfusion. The consistent results in ducks contrast with the equivocal data hitherto reported for central stimulations with NE or its agonists in mammals and may be due to the concentric perfusion system used in our study for localized stimulations in the vicinity of the paraventricular nucleus.

Osmotic and hormonal stimulation of the third ventricular region of ducks: antidiuretic, circulatory and local neuronal responses.

By means of local microperfusion of the 3rd cerebral ventricle, antidiuretic and circulatory responses to stimulations with various hypertonic solutions and norepinephrine were analyzed in conscious ducks. The results suggest ionic rather than osmometric responsiveness of periventricular osmoreceptive elements, which is in line with single unit recordings of periventricular neurons tested in vitro for their osmoresponsiveness. These neurons were located subependymally at the site of greatest responsiveness in vivo, and corresponded to morphologically identified neurons projecting to the neuroendocrine hypothalamo-pituitary system. Antidiuresis was combined with increases in arterial pressure and heart rate in response to hypertonic stimulations with monovalent cations; divalent cations produced long-lasting antidiuresis and equivocal circulatory responses. Norepinephrine elicited antidiuresis which was accompanied by arterial hypotension and bradycardia. Osmotically and norepinephrine induced antidiuresis was combined with increases of plasma ADH concentration. Different modulatory actions of intrinsic adrenergic, angiotensinergic and vasotocinergic neurons are suggested in hypothalamic control of autonomic functions.

Occlusion of rostroventral 3rd ventricle abolishes drinking but not AVP release in response to central osmotic stimulation.

Dogs were implanted with a device for chronic cannulation of the anterior part of the 3rd ventricle (A3V). Intracerebroventricular (i.c.v.) infusion of artificial cerebrospinal fluid (CSF) containing 0.35 M NaCl into the A3V of 7 normally hydrated dogs induced thirst (average water intake 11.8 +/- 2.0 ml.kg-1 b. wt.) and significantly increased arginine-vasopressin (AVP) concentration in the blood plasma from 3.4 +/- 0.3 to 8.2 +/- 1.2 pg.ml-1. When repeating the i.c.v. hypertonic infusion at intervals of one week or more in two dogs, its dipsogenic effect vanished within 3-5 months. X-ray analysis revealed an occlusion of the rostroventral part of the A3V. Subsequent controls on 3 other dogs confirmed that the dipsogenic response to i.c.v. osmotic stimulation was abolished in association with similar partial occlusions of the A3V. However, this stimulus still produced a significant increase of plasma AVP from 3.7 +/- 0.5 to 5.7 +/- 0.7 pg.ml-1 in the 5 dogs. Control of drinking in these dogs was otherwise unimpaired as indicated by their normal plasma osmolalities. Histological examination revealed that the loss of the dipsogenic response to i.c.v. infusion of 0.35 M NaCl was in each case associated with fibrinous occlusion of the A3V between its rostral wall and the mass intermedia, preventing the passage of the infusate to the supraoptic and infundibular recesses.

Central and systemic antidiuretic hormone and angiotensin II in salt and fluid balance of birds as compared to mammals.

1. Tonicity dominates the release of ADH with similar sensitivities (0.2-1 pg/ml per mOsm/kg) for both birds and mammals. 2. There is an inverse relationship between the volume of the extracellular fluid compartments and the plasma level of ADH. 3. Angiotensin II formation is governed by volume factors. 4. In birds the factors reducing the delivery of Na+ to the nephron distal tubules stimulate ANGII formation. 5. Mammals have a high vascular constrictor sensitivity to ADH and ANGII; there is little or no vascular sensitivity to these in birds. 6. In birds and mammals the subfornical organ and other circumventricular organs have receptors that specifically bind ANGII. 7. Dog and duck CSF levels of ADH and AII indicate their function as specific mediators of intrinsic neuronal systems controlling salt and fluid balance.

Gradient of arginine vasopressin concentration but not angiotensin II concentration between cerebrospinal fluid of anterior 3rd ventricle and cisterna magna in dogs.

Dogs were chronically implanted with two devices for cerebrospinal fluid (CSF) sampling from (a) the anterior part of the 3rd ventricle and (b) the cisterna magna. In conscious dogs arginine vasopressin (AVP) concentration of CSF samples collected at different occasions were 2-3 times higher in the CSF of the 3rd ventricle as compared to the AVP concentration of the cisterna magna. Inhalation anesthesia stimulated AVP release into the CSF at both sites by a factor of about 2, the gradient between 3rd ventricle and cisterna magna CSF of 2-3 remained for AVP in simultaneously collected samples. In contrast, angiotensin II-like immunoreactivity of CSF was not significantly different at both sites, neither in the conscious dogs nor during anesthesia. It is concluded that the main amount of AVP enters the CSF at the 3rd ventricular level.

Interaction of changes in the third ventricular CSF tonicity, central and systemic AVP concentrations and water intake.

Arginine vasopressin (AVP) is assumed to be involved as a central transmitter or modulator in the control of autonomic functions including thirst. In conscious dogs AVP concentration in cerebrospinal fluid (CSF) from the anterior part of the third ventricle (A3V) was analysed before and after local elevation of CSF osmolality by intracerebroventricular (i.c.v.) infusion of 0.35 M NaCl and after i.c.v. AVP infusion at 46 and 138 fmol ml-1 for 10 min. In addition, the effects of these i.c.v. infusions on water intake, plasma AVP concentration and blood pressure were investigated. In euhydrated dogs 0.35 M NaCl i.c.v. did not alter AVP concentration in the CSF during the subsequent 2 h. In contrast, plasma AVP concentration had increased significantly from 3.4 +/- 0.3 (control) to 6.4 +/- 0.7 and 4.7 +/- 0.3 fmol ml-1, 4 and 16 min, respectively, after the hypertonic stimulus. Drinking was stimulated with an average water intake of 14.5 +/- 3.7 ml kg-1 body wt. However, AVP infusion into the A3V did not elicit water intake despite increases of AVP concentration in the A3V by factors up to 40 above control. The same animals responded with spontaneous drinking to 0.35 M NaCl i.c.v. administered 160 min after the end of AVP infusions. Exogenously administered AVP disappeared from the A3V with a time constant of 13.8 min. The results do not support the view that AVP in the A3V CSF per se stimulates drinking.

Effect of bombesin on thermoregulation of the rabbit.

Injections of bombesin (BOM, 125, 250 and 500 ng) into the preoptic/anterior hypothalamus caused dose-related decreases of threshold temperatures for metabolic cold defence, cutaneous vasomotor tone and respiratory rate, combined with a reduced sensitivity of these thermoregulatory effectors in response to core temperature changes induced at thermoneutral or warm ambient conditions. Intracisternal (i.c.) injections of BOM (250 ng) produced qualitatively identical thermoregulatory effector changes in response to core temperature changes. Injections of BOM into the posterior hypothalamus did not affect body temperature control. Increased locomotor behavior, licking and grooming was elicited, however, from all injection sites. The results explain the prevailing hypothermic effect of BOM as the consequence of the concerted decrease in threshold temperatures and "gains" of all autonomic thermoregulatory effectors and suggest the activation of warm inputs, relative to cold inputs, at the hypothalamic level as the underlying mechanism. Direct or indirect inhibition of the intrinsic hypothalamic system involving thyrotropin-releasing hormone (TRH) and consequent deactivation of central noradrenergic pathways known to generate the entire autonomic pattern of cold defence might be involved in the neuro-humoral changes resulting in hypothermic effects of centrally applicated BOM.

Thermally induced changes in neural and hormonal control of osmoregulation in a bird with salt glands (Anas platyrhynchos).

In conscious Pekin ducks adapted to hypertonic saline (1.9%) as drinking water, steady state secretion of the salt glands was established by continuous intravenous salt loading and the effects of hypothalamic thermal stimulation on salt gland activity and on the plasma concentrations of arginine vasotocin (AVT) and angiotensin II (AII) were observed. Hypothalamic cooling depressed salt gland secretion and the plasma level of AVT. Hypothalamic warming caused transient activation and subsequent inhibition of salt gland secretion without consistent changes of the plasma levels of AVT and AII. Whole body cooling by heat extraction with a colonic thermode produced moderate inhibition of salt gland activity, without changes in plasma AVT and AII, which may be explained by peripheral vasoconstriction. The results are consistent with the view that hypothalamic osmoregulation is under an influence of local temperature by combined osmo/thermo-responsiveness of hypothalamic neurons and temperature dependence of signal transmission in hypothalamic neural integration of osmoregulation.